In recent years, the work in my lab and that of other investigators has revealed that so-called prefrontal function involves a broad network of areas including not only the prefrontal cortex but also the hippocampus, basal ganglia, and certain thalamic nuclei. These structures are anatomically connected in a particular way that is shared by rodents, humans, and non-human primates, suggesting a mammalian network underlying the forebrain control of behavior. Its relation to the regulation of neurotransmitters, such as dopamine, makes it central not only to understanding executive function, but also to schizophrenia and other disorders in humans. Our planned research is focused on understanding the functional anatomy of this circuitry. Our most recent studies have examined the function and connections of the hippocampus, which we now believe is at least as important as the prefrontal cortex for the inhibitory control of behavior. For example, like humans with disinhibitory symptoms (e.g., psychosis, alcohol use disorder, hyperkinesis), rats with hippocampal lesions are impulsive, antisocial, and emotionally unaroused. As this circuitry is central to our understanding of a wide range of human cognitive abilities and disorders, our future research will continue to investigate its underlying neurobiology, always retaining as its focal point the measurement and quantification of behavior. In the coming years, we will investigate the interaction between the hippocampus and the prefrontal cortex, as well as their convergent projections onto the nucleus accumbens, in certain types of decision-making behavior. Drawing from our toolbox of ablation, pharmacological blockade, and cell-type specific suppression or stimulation using genetically encoded agents, we will attempt to understand the specific types of decisions served by different pathways. For example, we recently found that some types of decisions, particularly those involving time, critically and specifically depend on the interaction between the ventral hippocampus and the nucleus accumbens (Abela et al., European J. Neurosci, 2015). For such decisions, the prefrontal cortex appears to play a relatively minor role. At the same time, the hippocampus works together with the prefrontal cortex in other categories of decisions, such as those requiring the inhibition of a prepotent response (Abela et al., Cerebral Cortex, 2013). Neurotransmitter and neuropeptide levels are known to selectively modulate the nature of this hippocampal contribution. For example, we were able to improve decision-making skills in control rats by pharmacologically stimulating the alpha-2a-receptors directly in the ventral hippocampus, whereas stimulating dopamine D1 receptors had no such effect (Abela and Chudasama, Psychopharm. 2014). This modulation of cognitive decision-making may be related to the successful use of noradrenergic stimulants to relieve symptoms of Attention Deficit Hyperactivity Disorder, where the site of action is presumed to be in the prefrontal cortex but never the hippocampus. In the past year, we have further explored the role of noradrenaline in cognitive function by focusing specifically on neuropeptides like Galanin and Neuropeptide Y, which are co-released with noradrenaline. Galanin receptors are highly expressed in the prefrontal cortex and the hippocampus and discovered that Galanin receptor 1 mediated neurotransmission in these areas modulate impulse control mechanisms (Messanvi et al., Pyschopharm, 2019). Further experiments targeting galanin receptor 1 specific cells in the hippocampus will provide insight into how temporal lobe structures interact with the prefrontal cortex to optimize behavioral control. We thus plan to investigate the contribution of the hippocampus more specifically using cell-type specific inactivation. For this, we plan to combine behavioral testing with optogenetic methods using a cre-dependent virus under the control of a galanin receptor 1 promotor. This reversible manipulation approach will allow us to gauge the relative contributions of the hippocampus, prefrontal cortex, and other related structures such as the nucleus accumbens and amygdala, to different types of cognitive decisions, with a high level of precision at both the behavioral and circuitry level. Understanding this interplay, as well as the effects of pharmacological agents in normalizing the contribution of these circuits, is a critical component of our research agenda that can have a direct clinical impact. In addition to the hippocampus, the thalamus has been increasingly recognized as contributing not only to the transmission of sensory and movement-related signals but also to aspects of executive function. This is particularly true of its midline nuclei, most of which have not been studied in great detail. We recently tracked putative pathways through the thalamus from the prefrontal and limbic cortex to the hippocampus using a polysynaptic virus (Prasad and Chudasama, J. Neurosci. 2013). We found that different regions of the hippocampus received input from different thalamic nuclei, which in turn received input from different cortical structures. This finding raised the question as to whether the midline thalamus is an important hub in frontotemporal circuitry, and by extension, to what extent is it a critical contributor to executive function? This question became more pressing in light of recent findings from our laboratory that ablation of one of these principal relay nuclei, the nucleus reuniens, leads to significant changes in executive behavior. Specifically, and somewhat paradoxically, we found that lesions to this structure improved animals capacity to perform on cognitive tasks by making them intensely focused, less impulsive and highly motivated (Prasad et al., 2017). To get a better understanding of how the thalamus interacts with frontal and temporal structures, we conducted a series of anatomical studies to trace the connections of different thalamic structures using neurotrophic viruses such as pseudorabies (PRV), an alpha herpesvirus. These viruses are self-amplifying neuronal markers of polysynaptic neural connectivity and therefore have the capacity to delineate circuits or pathways of connected neurons by expressing fluorescent tags such as red dTomato (PRV-614) or green fluorescent protein (PRV-152) at each synaptically connected neuron. This work has identified a topographical arrangement of cortical connections of the dorsal and ventral midline thalamic structures suggesting that the so-called non-specific midline thalamus is very specific in how it interacts with different brain regions. The behaviors following lesions of the prefrontal cortex, nucleus reuniens, and hippocampus underscore the fact that the control of executive behavior involves a broad network of structures, some of which lie outside the cortex and even outside of the telencephalon. Based on known connections and neuropharmacology, we anticipate that our understanding of this network will continue to expand and include additional brain structures, for example, particular nuclei in the hypothalamus and the septum. In fact, some preliminary neuroanatomical data shows that the ventral portion of the lateral septum receives substantial input from ventral hippocampus and prefrontal cortex. We also recently discovered that permanent ablations of the ventral lateral septum, not only cause significant emotional changes, they result in substantial morphological changes within the prefrontal cortex and ventral hippocampus, which varied as a function of sex. Of particular interest is the high density of androgen receptors present in the hippocampus and the putative contribution of the septohippocampal system in cognitive and emotional development.